1. Field of the Invention
The present invention relates generally to the field of immunology and more particularly to methods and compositions for inhibiting complement mediated inflammatory reactions.
2. Description of the Related Art
The complement system is a major effector system of host defense against infectious microorganisms. It is composed of more than 30 plasma and membrane proteins which when activated, result in the generation of biologically active peptide fragments and protein complexes which promote acute inflammation, enhance the clearance of microorganisms by host phagocytic cells, and directly kill invading pathogens.
The complement system can be activated via two pathways, an antibody-dependent pathway called the classical pathway and an antibody-independent pathway called the alternative pathway (1,2). Activation of either pathway results in the assembly of enzymes called C3 convertases which cleave complement component C3 at a single peptide bond to form C3a and C3b. Some of the C3b molecules then bind to the C3 convertases changing their substrate specificity such that they now cleave C5 to C5a and C5b. All of the biological activities of the complement system, in turn, are derived from the cleavage products of C3 and C5.
Several cell surface proteins have been described which regulate complement activity and protect cellular elements of host tissues from complement mediated injury. These include membrane cofactor protein (MCP)/CD46, decay accelerating factor (DAF), membrane inhibitor of reactive lysis (MIRL)/CD59, and homologous restriction factor (HRF)/C8-binding protein (18-24).
C1q is a subcomponent of the C1 complex, the first component of the classical pathway of complement activation (25). Certain matrix proteins have been shown to bind C1q including fibronectin (40, 41), laminin (42), and fibrin (43). These interactions are saturable and appear to be specific; however, with the exception of laminin, binding of C1q to these proteins has been demonstrated only under conditions of low ionic strength. Furthermore, the interaction of C1q with these matrix proteins has not been demonstrated to alter the activity of C1, thus, their biological relevance is uncertain.
Though the integrity of the complement system is necessary for effective protection against infectious organisms, when excessively activated or misdirected, complement-mediated inflammation can result in damage to host tissues. For example, complement-mediated inflammation has been demonstrated to produce host tissue damage in animal models of autoimmune diseases such as collagen-induced arthritis (8, 9), myasthenia gravis (10, 11), and membranous nephropathy (12, 13). Complement activation also, in part, mediates the tissue destruction which occurs following myocardial infarction (14, 15) and burn injuries (16, 17).
While advances have been made in our understanding of the regulation of complement-mediated inflammation, there is presently no satisfactory way to inhibit complement activation and protect the host tissues in an autoimmune inflammatory response. There exists a particular need for the identification of substances that are both well tolerated with few side effects that are effective in inhibiting or suppressing complement-mediated immune responses.